FILGRASTIM SD/01 IN NONSMALL CELL LUNG CANCER

目的：本I期研究的主要目的是比较 安全性、剂量反应、药效学和药代动力学特性 非格司亭-SD/01改为非格司亭。尚未对非格司亭-SD/01进行检测 在人类身上。 非格司亭-SD/01是非格司亭（G-CSF，Neupogen）共价连接 在N-末端与聚乙二醇（PEG）分子结合。 蛋白质的聚乙二醇化降低了清除率并增加了半- 化合物的寿命，导致持续的持续效果。 Filgrastim 是一种谱系特异性造血生长因子， 刺激中性粒细胞的生长、分化和功能。它有 已被FDA批准用于化疗诱导的中性粒细胞减少症，骨髓 移植、严重慢性血小板减少和干细胞动员。 非格司亭-SD/01的优点是， 与重复注射非格司亭相同， 单次注射。潜在的好处包括更少的注射， 增加患者依从性，在一段时间内不间断治疗 当病人不能去诊所就诊时， 支助人员。 方法：本研究针对非小细胞肺患者， 需要化疗的癌症研究将分两部分进行，给药 卡铂/紫杉醇治疗1个周期前后使用研究药物 化疗研究的总持续时间为五周。 患者 将随机（3：1）接受非格司亭-SD/01或Neupogen 在整个研究中。在A部分化疗前，患者随机化 接受研究药物的受试者将根据剂量接受一次注射 第一天的任务。随机分配至G-CSF组的患者将接受 皮下注射5 ug/kg/天，持续5天或直至ANC 达到75，000。患者将连续12天每天抽血 用于常规血细胞计数和化学、药代动力学和CD 34 分析.化疗将包括卡铂（AUC为6，30 min 输注）加紫杉醇（24小时输注，225 mg/M2）。二十四小时 化疗完成后，患者将接受研究药物或G- A部分给药剂量的CSF。接受G-CSF治疗的患者将在5 直至ANC > 10，000。每天抽血15天 在部分B期间连续进行，以进行与部分A类似的分析。 药代 和药效学方法将用于比较G-CSF和非格司亭- SD/01，A和B部分。将使用描述性统计量 表征A部分期间的中性粒细胞和CD 34计数。广义 将使用线性模型估计非格司亭-SD/01 剂量对B部分中性粒细胞应答的影响。这种中性粒细胞反应将是 通过对G-CSF救援的需要以及严重 中性粒细胞减少症。每个给药组中需要 将对G-CSF补救治疗与患者比例进行连续性比较 G-CSF组中符合抢救标准的患者。

PURPOSE: The primary objectives of this phase I study are to compare the safety, dose response, pharmacodynamic and pharmcokinetic properties of filgrastim-SD/01 to filgrastim. Filgrastim-SD/01 has not yet been tested in humans. Filgrastim-SD/01 is filgrastim (G-CSF, Neupogen) covalently bound at the N-terminus with a polyethylene glycol (PEG) molecule. Pegylation of a protein decreases the clearance and increases the half- life of compounds, resulting in a sustained duration effect. Filgrastim is a lineage-specific hematopoietic growth factor that preferentially stimulates the growth, differentiation and function of neutrophils. It has been approved by the FDA for chemotherapy-induced neutropenia, bone marrow transplantation, severe chronic neutropenic and stem cell mobilization. Filgrastim-SD/01 offers the advantage that similar pharmacologic effects identical to repeat injections of filgrastim can be obtained from a single injection. Potential benefits would include fewer injections, increased patient compliance, uninterrupted therapy over periods of time when the patient cannot visit clinics, and reduced burden on medical support staff. METHODS: This study is directed at patients with non-small cell lung cancer requiring chemotherapy. The study will be done in two parts, dosing with study drug pre and post one cycle of carboplatin/paclitaxel chemotherapy. The total duration of the study is five weeks. Patients will be randomized (3:1) to receive either filgrastim-SD/01 or Neupogen throughout the study. During part A, pre-chemotherapy, patients randomized to receive study drug will receive one injection according to dose assignment on day 1. Patients randomized to G-CSF will receive subcutaneous injections at 5 ug/kg/day for five days or until the ANC reaches 75,000. Patients will have daily blood draws for 12 days in a row for routine blood counts and chemistries, pharmacokinetics, and CD34 analysis. The chemotherapy will consist of carboplatin (AUC of 6, 30 min infusion) plus paclitaxel (24 hour infusion, 225 mg/M2). Twenty-four hours after completion of chemotherapy, patients will receive study drug or G- CSF at the dose given in part A. Patients on G-CSF will be dosed at 5 ug/kg/day until ANC > l0,000. There will be daily blood draws for 15 days in a row during part B for analyses similar to part A. Pharmacokinetic and pharmacodynamic methods will be used to compare G-CSF and filgrastim- SD/01 in parts A and B. Descriptive statistics will be used to characterize the neutrophil and CD34 counts during part A. Generalized linear models will be used to estimate the association of filgrastim-SD/01 dose on neutrophil responses in part B. This neutrophil response will be measured by the need for G-CSF rescue as well as duration of severe neutropenia. The proportion of patients in each dosing group who require G-CSF rescue will be descriptively compared to the proportion of patients in the G-CSF group who met the criteria for rescue.